The Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) will be a new consortium established to undertake immunologic research directed at tackling major scientific problems that hinder the development of an effective HIV-1 vaccine. Over the next 7 years, the CHAVI-ID will build on the progress made by the CHAVI consortium and apply state-of-the-art technologies and both immunologic and virologic tools to improve rational HIV-1 vaccine design. Our vaccine strategy will be based on identifying and targeting novel HIV-1 vulnerabilities to B, T and NK cell immune responses and then using this information to design vaccines that will induce protective immunity at the time and location of HIV-1 transmission. The overall CHAVI-ID goals are to design immunogens that prevent HI V-1 transmission by inducing innate, antibody as well as CD4+ and CD8+ T cell responses at the site of HIV-1 entry. Since the components of the human immune system work in concert, the final goal of the CHAVI-ID is to design a practical preventive HIV-1 vaccine that incorporates protective innate, antibody and T cell-targeted immunogens. CHAVI-ID will be led by the CHAVI-ID principal investigator and scientific leadership group along with CHAVI-ID leaders of 11 Scientific Research Support Components and an experienced Operations and Management Support Component. The centerpiece of our CHAVI-ID research agenda is the Research Program which has three Foci: 1. Induction of Protective Antibody Responses, 2. Induction of Protective T Cell Responses and 3. Induction of Protective Innate Responses-all of which are derived directly from discoveries made during the past 6 years of the Center for HIV/AIDS Vaccine Immunology (CHAVI) grant, and together constitute a clear path to overcoming the remaining obstacles preventing development of an effective preventive vaccine. CHAVI-ID Organization: The CHAVI-ID will be a component of the Global HIV-1 Enterprise comprised of outstanding investigators using state-of-the art technology that will address critical gaps in scientific knowledge through focused, coordinated studies ultimately targeted at making a successful HlV-1 vaccine. CHAVI-ID will initially work to identify innate, T, and B cell protectie immune responses by studying samples obtained from completed human vaccine efficacy trials, and by carrying out passive and active immunization trials to prevent infections by R5 SHIVs in rhesus macaques. CHAVI-ID investigators will define structures of protective HIV-1 envelope (Env) epitopes using crystallography and single particle cryoelectron microscopy, design vaccine strategies for driving antibody maturation pathways of difficult-to-induce neutralizing antibodies, as well as.design vaccine strategies for expanding the breadth and depth of induced T cell responses. CHAVl-ID will have an administrative structure that facilitates eliminating unsuccessful programs and acquiring new expertise as they are needed. CHAVI-ID studies of protective immune responses in vaccinees will be supported by long-term and ongoing research agreements and collaborations with the HIV Vaccine Trials Network (HVTN), the NIH Vaccine Research Center (VRC) and the Military HIV Research Program (MHRP). CHAVI-ID will be led by the CHAVI-ID principal investigator and scientific leadership group along with CHAVl-lD leaders of 12 Scientific Research Support Components (SRSCs) (Table 1). The CHAVI Principal Investigator (PI) is Barton Haynes at Duke University. He has chosen five leaders to join the CHAVI Scientific Leadership Group (SLG): Garnett Kelsoe from Duke University, Bette Korber from Los Alamos National Laboratory, Norman Letvin from Harvard University, Andrew McMichael from Oxford University and Joseph Sodroski from Harvard University. RELEVANCE: Much progress has been made over the past 6 years in overcoming roadblocks to development of a safe and effective HIV-1 vaccine. However, a number of roadblocks remain. By study of immune responses made by HIV-1 clinical trial vaccinees in a modestly successful HIV-1 vaccine trial (RV144), and by study of HIV-1-infected people who eventually make the desired immune responses, a path to overcoming the final roadblocks can be charted, and improved vaccine candidates designed for new clinical trials. OVERALL UM-1 CENTER APPLICATION: